Table Info

Table 1.

Summary of different cell types and their role in the normal and leukemic HSC niches

Cell type	Secreted or expressed factors (molecular pathways)	Healthy niche	AML niche	Altered molecular pathways
Non-hematopoietic cells
Osteoblasts	CSF3 BMPRIA Osteopontin/CD44	Control HSC expansion and self-renewal Regulation of HSC homing, quiescence, and mobilization Control the generation of adaptive immune cells	AML decreases osteoblast production AML decrease OSP AML increases CD44 expression	Unchecked activation of the RANK/RANKL pathway
Osteocytes	CSF3 (indirect way)	Regulation of osteoblast	-	-
Nestin⁺ mesenchymal cells	CXCL12 SCF	Differentiation to osteoblast, chondrocytes and adipocytes Enhance HSC differentiation and maintenance of HSC Mediate sympathetic circadian signaling to HSC	MSCs increase CD271⁺ MSCs JAG1 MSCs decrease SCF Enhancement of BM homing of AML LSCs Supporting low proliferative but highly resistant LSCs	CXCL12/CXCR4
CAR cells	CXCL12	Maintaining HSC Maintaining lymphoid progenitors	CXCR4 expression is increased by AML blast CXCL12 secretion is increased by CAR cells	CXCL12/CXCR4 Activation of JAK/STAT, PI3K/AKT, and MEK/ERK pathways through CXCL12/CXCR4
Non-myelinating Schwann cells	TGFB (SMAD) signals	HSC quiescence	Disruption of nestin GFP⁺ cell quiescence	-
SNS	Catecholamines	Controlling the cyclical circadian release of HSCs	SNS denervation enhances leukemic cell proliferation	Altered B2-adrenergic pathway
Adipocytes	Adiponectin	Negative regulators of homeostatic	AML cells increase lipolysis AML cells increase FAO	GDF15 is highly expressed by LSCs Upregulation of PPARG, FABP4, and BCL2 genes by LSCs
Endothelial cells	Selectin E Selectin P VCAM1 Express Notch ligands	Doorkeeper Maintaining HSCs Increase HSC quiescence and self-renewal	Promote adhesion of LSCs Stimulates AML cells and proliferation Angiogenesis	Notch pathway CD44/Selectin E VLA4/VCAM1 DLL4 pathway
Hematopoietic cells
Osteoclast	RANKL pathway Proteolytic enzymes	Maintenance of the endosteal niche cavities HSC mobilization Osteoclast depletion is associated with an increase in EH	-		-
Macrophages	Oncostatin M Prostaglandin E2	HSCs mobilization HSCs retention in the endosteal niche Macrophages increase CXCL12/CXCR4 by nestin⁺ MSCs Promote Erythropoiesis	LAM helps in chemotherapeutic resistance		-
Lymphocytes	-	Regulation of hematopoietic stem cell growth T-regs play a crucial role in immune tolerance T-regs create a protective zone from the immune attack	AML dysregulates T-cells AML evades detection by NK cells Exhaustion of CD8⁺ T-cells Dysregulation in Th1/Th2 axis Increase in dysregulation in Th1/Th2 axis and its cytokines AML increase T-regs AML stimulates T-regs		TIM3/LGALS9 ICOSLG
Neutrophils	Indirect role mediated by macrophages	Clearance of aged neutrophils by macrophages regulates HSCs mobilization	-		-

HSC: hematopoietic stem cell; AML: acute myeloid leukemia; RANK: receptor activator of nuclear factor κB; RANKL: receptor activator of nuclear factor κB ligand; MSCs: mesenchymal stromal cells; BM: bone marrow; LSCs: leukemic stem cells; CAR: CXCL12-abundant reticular; TGFB: transforming growth factor-beta; GFP: green fluorescent protein; FAO: fatty acid β-oxidation; EH: extramedullary hematopoiesis; LAM: leukemia-associated macrophage; NK: natural killer; T-regs: regulatory T-cells; BMPRIA: bone morphogenetic protein receptor type IA; VCAM1: vascular adhesion molecule 1; SNS: sympathetic nervous system; VLA4: very late antigen 4; GDF15: growth differentiation factor 15; OSP: osteopontin. -: no data

Declarations

Author contributions

SK: Conceptualization, Writing—original draft, Writing—review & editing. MES and AEG: Data collection. GV: Funding acquisition. PPP: Supervision.

Conflicts of interest

Pier Paolo Piccaluga is the Editorial Board Member of Exploration of Targeted Anti-tumor Therapy and Guest Editor of Mechanisms of Targeted Therapy Resistance and Reversal Strategies, but he had no involvement in the journal review process of this manuscript. The other authors declare that there is no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

The work reported in this publication was funded by the Italian Ministry of Health [RC-2023-2778976, PRIN 2022NXK38S, and FIRB Futura 2011 RBFR12D1CB]. Giuseppe Visani received the support of AIL Pesaro Onlus. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

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